Association between maternal exposure to PM10 and polydactyly and syndactyly: A population-based case-control study in Liaoning province, China.

BACKGROUND: The number of studies on air pollution with birth defects as the primary outcome has increased dramatically over the past two decades, but the potential role of specific air pollutants in congenital limb anomalies remains unclear. OBJECTIVES: To evaluate associations between preconception and first-trimester PM10 exposure and polydactyly and syndactyly in a population-based case-control study. METHODS: Polydactyly cases (n = 2605), syndactyly cases (n = 595), and controls without any birth defects (n = 7950) born between 2010 and 2015 were selected from the Maternal and Child Health Certificate Registry of Liaoning Province. The monthly mean PM10 concentrations were obtained from 75 air monitoring stations, and the exposure assessment was based on the mean concentration of all stations in mother's residential city. A multivariable logistic regression model was constructed to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: PM10 exposure was positively associated with the risks of polydactyly (preconception: aORT3 vs. T1 = 1.95, 95% CI 1.56-2.45, aOR = 1.06, 95% CI 1.01-1.10 [per 10-µg/m3 increment]; first-trimester: aORT3 vs. T1 = 2.51, 95% CI 2.00-3.15) and syndactyly (preconception: aORT3 vs. T1 = 2.86, 95% CI 1.98-4.13, aOR = 1.11, 95% CI 1.03-1.20 [per 10-µg/m3 increment]; first-trimester: aORT3 vs. T1 = 3.10, 95% CI 2.11-4.56). Analyses based on single month exposure windows basically showed similar positive associations. Additionally, these findings were robust in sensitivity analyses and broadly consistent across subgroups. CONCLUSION: Our study suggest that preconception and first-trimester PM10 exposures are related to increased risks of polydactyly and syndactyly.

The effects of microduplication 1q21.1 and in-utero isotretinoin exposure.

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.1 2 Due to the low numbers of in-utero isotretinoin exposed pregnancies, the interactions between this drug and rare genetic defects such as microduplication 1q21.1 are unclear, particularly how they might manifest phenotypically. We present this case of in-utero isotretinoin exposure occurring in a child with microduplication 1q21.1. The child was born with congenital abnormalities which did not fit into a single syndrome. Regrettably in-utero exposure to isotretinoin continues to occur. We hope this case will trigger further discussion on the dangers of dispensing Isotretinoin without ensuring stringent pregnancy testing and its potential interaction with genetic abnormalities, in particular with microduplication 1q21.1.

Possible association between acetazolamide administration during pregnancy and multiple congenital malformations.

Congenital malformations might occur because of environmental or genetic factors, and sometimes occur because of unknown causes. Acetazolamide is a carbonic anhydrase inhibitor that is used to treat idiopathic intracranial hypertension, glaucoma, and epilepsy. The use of acetazolamide has not been recommended for pregnant women because of reported teratogenic risks. Congenital malformations, such as ectrodactyly, syndactyly, cleft lip/palate, and retarded incisor teeth development, have been reported in experimental animals. However, tooth agenesis due to the use of acetazolamide has not been reported yet. Oligodontia is a severe type of tooth agenesis involving six or more congenitally missing teeth. The causes of oligodontia are attributed to environmental factors, such as irradiation, drugs, trauma, tumors, infection, genetic factors, or a combination. There is no credible evidence of undesirable effects of acetazolamide use in human pregnancy. However, we report a case of a 12-year-old Saudi boy who was exposed to maternal acetazolamide (1,000 mg/day) for treatment of idiopathic intracranial hypertension before pregnancy, during the first trimester, and throughout the pregnancy. This treatment might have resulted in some congenital malformations, such as ectrodactyly, syndactyly, and oligodontia.

Síndrome de Moebius, comunicación interventricular asociado a exposición prenatal a misoprostol / Moebius Syndrome, ventricular septal defect due to prenatal exposure to misoprostol

Introducción: El síndrome o secuencia de Moebius se caracteriza por la afectación del nervio facial y nervio abducens y puede estar asociado a defectos congênitos orofaciales y de las extremidades. Adicionalmente en las dos últimas décadas se han reortada una posible asociación con exposición prenatal a misoprostol. Objetivo: Presentar un caso de síndrome de Moebius con cardiopatía compleja (comunicación interventricular y pseudocoartación de aorta) asociado a exposición prenatal a misoprostol. Caso clínico: Paciente de 5 años quien consulta por antecedente de retardo en el desarrollo psicomotor, anomalías craneofaciales, cardiacas y de las extremidades, con antecedente de exposición prenatal a misoprostol, a quien se le diagnóstica síndrome de Moebius. Conclusiones: Aunque la etiología de este síndrome no es clara, un mecanismo fisiopatológico involucrado es el de la hipoxia que puede ser secundario a la exposición prenatal a misoprostol.

Introduction: Moebius syndrome/sequence is characterized by facial and abducens nerve damage and may be associated with congenital orofacial and limb defects. Additionally, in the last two decades, a possible association with prenatal exposure to misoprostol has been reported. Objective: To present a case of Moebius Syndrome with complex heart disease (ventricular septal defect and pseudocoarctation of the aorta) associated with prenatal exposure to misoprostol. Case report: A 5 year old patient diagnosed with Moebius Syndrome who consulted specialists due to psychomotor retardation, craniofacial, heart and limb defects, and with a history of prenatal exposure to misoprostol is presented. Conclusions: Although the etiology of this syndrome is not clear, hypoxia is a pathophysiological mechanism involved, which can be secondary to prenatal exposure to misoprostol.

Busulfan-induced central polydactyly, syndactyly and cleft hand or foot: a common mechanism of disruption leads to divergent phenotypes.

The prevalence of clinical phenotypes that exhibit combinations of central polydactyly, syndactyly, or cleft hand or foot is higher than would be expected for random independent mutations. We have previously demonstrated that maternal ingestion of a chemotherapeutic agent, busulfan, at embryonic day 11 (E11) induces these defects in various combinations in rat embryo limbs. In an effort to determine the mechanism by which busulfan disrupts digital development, we examined cell death by Nile Blue staining and TdT-mediated dUTP nick end labeling (TUNEL) assays; we also carried out whole mount in situ hybridization for fibroblast growth factor-8 (Fgf8), bone morphogenetic protein-4 (Bmp4), and sonic hedgehog (Shh) to examine developmental pathways linked to these defects. In busulfan-treated embryos, diffuse cell death was evident in both ectoderm and mesoderm, peaking at E13. The increased cell death leads to regression of Fgf8 in the apical ectodermal ridge (AER) and Bmp4 and Shh in the underlying mesoderm. The subsequent pattern of interdigital apoptosis and cartilage condensation was variably disrupted. These results suggest that busulfan manifests its teratogenic effects by inducing cell death of both ectoderm and mesoderm, with an associated reduction in tissue and a disruption in the generation of patterning molecules during critical periods of digit specification.

The possible association between the combination of vaginal metronidazole and miconazole treatment and poly-syndactyly Population-based case-control teratologic study.

The objective of the study was to investigate the human teratogenic potential of vaginal metronidazole+miconazole treatment during pregnancy, because these antimicrobial drugs separately did not indicate human teratogenic potential in our and other studies. The analysis of cases with 21 groups of congenital abnormalities and their all matched controls was carried out in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996 including 38,151 pregnant women who had newborn infants without any congenital abnormalities (control group) and 22,843 pregnant women who had newborn infants or fetuses with congenital abnormalities. The prevalence of vaginal metronidazole+miconazole treatment during pregnancy was 2.5% (N=576) in the case group and 2.2% (N=846) in the control group [crude prevalence odds ratio (POR) with 95% confidence interval (CI): 1.2, 1.0-1.3]. The analysis of cases and their matched controls indicated an association between vaginal metronidazole+miconazole use and poly/syndactyly during the second through third months of gestation (adjusted POR 6.0, 95% CI 2.4-15.2). This finding may be connected with recall bias, although this bias was restricted by the evaluation of maternal drug use only during the critical period of poly/syndactyly and by evaluating only medically recorded metronidazole+miconazole treatment. The conclusion of the study is that this finding can be regarded as a signal for the possible association between vaginal treatment of metronidazole+miconazole during pregnancy and poly/syndactyly without any plausible biological hypothesis.

Teratogenic mechanisms of longitudinal deficiency and cleft hand.

In order to better understand the teratogenic mechanisms of congenital defects of the digits, we analyzed clinical cases and induced similar types of congenital hand anomalies in rat fetuses by oral administration of busulfan. In clinical cases, radial and ulnar deficiencies had common characteristic features. We induced radial and ulnar deficiencies in rat fetuses with the same drug. Radial and ulnar deficiencies induced in rats have similar clinical manifestations and these anomalies might be caused by the same teratogenic mechanism. Then, the formation of the digital rays was examined histologically. The results of histological examination suggested that these deficiencies were not caused by localized damage of the limb bud. They also suggested that the cause of missing digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells in the limb bud. Cleft hand is considered to be one of the types of longitudinal deficiency. However, several investigators have suggested that the abnormal induction of finger rays in the process of formation of fingers induced central polydactyly, osseous syndactyly and also cleft hand. X-rays of the clinical cases and skeletal changes of the anomalies induced in rats appear to demonstrate that cleft hand formation proceeds from osseous syndactyly and central polydactyly. The results of our experimental study show that the critical periods of central polydactyly, osseous syndactyly and cleft hand are the same. They also suggest that central polydactyly, syndactyly and cleft hand might be induced when the same teratogenic factor acts on embryos at the same developmental stage in the human being. Because they have a similar causation, cleft hand, syndactyly and central polydactyly should be classified into the same entity, that is, abnormal induction of digital rays. Based on these clinical and experimental studies, we modified the Swanson classification. In our modified classification, typical cleft hand, syndactyly and polydactyly are included in the same category of abnormal induction of digital rays as the fourth new category.

Influence of anaesthetic agent on limb abnormalities observed following amniotic sac puncture.

In all of our previous studies into the effect of amniotic sac puncture (ASP) carried out on day 13 of pregnancy in mice, we have used intraperitoneal Avertin (tribromoethanol) as the general anaesthetic. In the present study, we used an inhalational anaesthetic (a mixture of halothane, oxygen and nitrous oxide in a ratio of 2:3:3). The principal difference between these two regimens is that even under optimal post-operative conditions when Avertin is used it can take between 45 and 90 min before complete recovery is achieved; when the inhalational anaesthetic is used, complete recovery is usually achieved within about 3-5 min. Because the experimental conditions were otherwise identical, this allowed the influence of the anaesthetic employed during ASP and the incidence of abnormalities induced on survival rate to day 19 of pregnancy to be studied. The survival rate was slightly higher when the inhalational anaesthetic was used, as was the incidence of limb abnormalities, although the overall incidence of gross abnormalities involving the palate, limbs and tail was not significantly different. The most marked difference, however, was in the incidence of syndactyly, which was significantly lower when the inhalational compared to the intraperitoneal anaesthetic was used: 26.6% v. 70.2% of the abnormal limbs analysed. A possible hypothesis is presented to explain this difference.

Safety of fluorescein angiography during pregnancy.

We sent 424 retina specialists questionnaires on fluorescein angiography performed on pregnant women; 399 specialists responded. Of these, 309 (77%) had never performed fluorescein angiography on a pregnant woman. Ninety specialists (23%) had performed at least one fluorescein angiogram on a pregnant woman; detailed information was obtained on 105 patients. Authors of previous reports that included fluorescein angiography during pregnancy provided information about an additional 11 patients. Substantiated side effects were nausea or vomiting in seven patients. Anomalies at birth, an undescended testicle and syndactyly, were reported in two children. There was one stillbirth with pathologic findings classic for toxemia, and one fetal death occurred several months after fluorescein angiography. One therapeutic abortion was performed for complications in toxemia. One spontaneous abortion occurred three days after fluorescein angiography in a patient who was four weeks pregnant. Eight children born to toxemic mothers had low birth weights. We conclude that fluorescein angiography does not cause a high rate of birth anomalies or complications during pregnancy.

Steroid contraceptive use and pregnancy outcome.

Contraceptive use in relation to pregnancy outcome was studied in 8,816 births in Chiang Mai, northern Thailand, by examination of newborn infants and interviews with their mothers. Four thousand twenty-three women used no contraception before the index pregnancy, 1,229 used the injectable contraceptive Depo Provera (DMPA), and 3,038 used oral contraceptives prior to or during pregnancy. No differences were observed between these groups with respect to still births, multiple pregnancies, and birthweight. Women who used oral contraceptives had unexpectedly low rates of major defects and may have been affected by self-selection bias, whereas the noncontraceptors had rates similar to other populations. There was a significantly increased association of polysyndactyly among infants of DMPA users relative to the other groups, which was most pronounced in offspring of women under age 30 years, and persisted after exclusion of subjects with a family history or infants with multiple abnormalities. However, in five out of the ten polysyndactyly cases, the last injection of DMPA occurred more than 9 months before conception, and only three cases had definite gestational exposure. The association of chromosomal anomalies was also significantly increased in infants of mothers who used DMPA. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptional exposure to DMPA in many cases, and chance effects due to multiple statistical comparisons make a causal association unlikely. Other birth defects that had been previously reported in some publications to be associated with progestational steroid exposure, such as neural tube defects, heart malformations, and limb reduction defects, were not found in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Syndactyly induced by Janus Green B in the embryonic chick leg bud: a reexamination.

In an attempt to clarify the mechanism of production of the syndactyly induced by Janus Green B (JGB) we have studied the morphology and structural modifications of the chick embryo leg bud after JGB administration by means of neutral red vital staining, whole-mount cartilage staining and light microscopy and transmission and scanning electron microscopy. The results show that the well-known inhibition of interdigital cell death is accompanied by a precocious alteration of the epithelial tissue and especially of the epithelial-mesenchymal interface. 24 h after JGB administration the cells of the AER reduce the number of junctions and the basal ectodermal cells are detached into the mesenchymal tissue in zones in which the basal lamina undergoes disruption. In addition the interdigital mesenchymal cells diverted from the dying program are able to undergo a rapid differentiation into cartilage. It is proposed that the mechanism of production of JGB-induced syndactyly might be due to an alteration of the normal epithelial-mesenchymal interactions rather than to a direct inhibitory effect of the JGB on the dying program.

[Pralidoxime prevents certain teratogenic effects induced by bidrin in quail embryos]. / Prévention par la pralidoxime de certains effets tératogènes induits par le bidrin chez l'embryon de caille

Bidrin treatment of quail embryos results in axial anomalies as well as malformations of the beak and the limbs. Whereas the administration of pralidoxime to teratogen-treated embryos prevents the appearance of the axial anomalies, the morphogenesis of the beak and limbs remains profoundly altered.